Microfluidic outer blood–retinal barrier model for inducing wet age-related macular degeneration by hypoxic stress

Abstract

Wet Age-related macular degeneration (AMD) is a severe ophthalmic disease developed in the outer blood-retinal barrier(oBRB), composed of two cells, the retinal pigment epithelium(RPE) and the choriocapillaris endothelium(CCE). Unfortunately, the...

Generation of a 3D Outer Blood–Retinal Barrier with Advanced Choriocapillaris and Its Application in Diabetic Retinopathy in a Microphysiological System

“…The optimized condition, 5 ng/mL VEGF supplementation in media, showed less regression of choroidal capillaries on the side of RPE and the lowest permeability coefficient. Although the permeability coefficient was still higher than the level in vivo, it was improved by an order of magnitude compared to our group’s previous study . The increase in the permeability coefficient in the condition without additional VEGF in media was presumed that the regression of choroidal blood vessels was a result of the apoptosis of vascular endothelial cells due to VEGF reduction, , and then the inability of clearance of apoptotic cells induced inflammation …”

“…Although the permeability coefficient was still higher than the level in vivo, 49 it was improved by an order of magnitude compared to our group's previous study. 19 The increase in the permeability coefficient in the condition without additional VEGF in media was presumed that the regression of choroidal blood vessels was a result of the apoptosis of vascular endothelial cells due to VEGF reduction, 50,51 and then the inability of clearance of apoptotic cells induced inflammation. 52 We identified relevant oBRB-choriocapillaris markers to confirm that our optimized model reflects in vivo oBRBchoriocapillaris (Figure 4).…”

“…Some studies did not consider several fundamental characteristics of oBRB and choriocapillaris. Specifically, they did not verify the presence of Bruch's membrane, which is composed of collagen IV and laminin, [17][18][19]21 or confirm the barrier function of oBRB using dextran or TEER. 20,21 Moreover, the previous studies did not verify the polarization of RPE cells or the fenestration of choriocapillaris.…”

“…Some studies did not consider several fundamental characteristics of oBRB and choriocapillaris. Specifically, they did not verify the presence of Bruch’s membrane, which is composed of collagen IV and laminin, − , or confirm the barrier function of oBRB using dextran or TEER. , Moreover, the previous studies did not verify the polarization of RPE cells or the fenestration of choriocapillaris. − In addition, several studies developed models that deviated from the physiological structures of oBRB and choriocapillaris, which could lead to different intercellular interactions compared to the in vivo environment. Especially, there were studies using an artificial membrane between RPE cells and a large blood vessel which is different in scale from the choriocapillaris, − , and a study using a thick acellular fibrin channel placed between RPE cells and choriocapillaris with separate fibroblast channels .…”

“…With these advantages, microphysiological systems are suitable for modeling oBRB and choriocapillaris in vitro. Several recent studies have developed oBRB-choriocapillaris models using microfluidic devices. − Although previous studies on oBRB-choriocapillaris models had their respective strengths, limitations still remained. Some studies did not consider several fundamental characteristics of oBRB and choriocapillaris.…”